Heat shock proteins (HSPs) are a class of chaperone proteins that are up-regulated in response to elevated temperature and other environmental stresses, such as ultraviolet light, nutrient deprivation, and oxygen deprivation. HSPs act as chaperones to other cellular proteins (called client proteins) and facilitate their proper folding and repair, and aid in the refolding of misfolded client proteins. There are several known families of HSPs, each having its own set of client proteins. The Hsp90 family is one of the most abundant HSP families, accounting for about 1-2% of proteins in a cell that is not under stress and increasing to about 4-6% in a cell under stress. Inhibition of Hsp90 results in degradation of its client proteins via the ubiquitin proteasome pathway. Unlike other chaperone proteins, the client proteins of Hsp90 are mostly protein kinases or transcription factors involved in signal transduction, and a number of its client proteins have been shown to be involved in the progression of cancer.
DNA topoisomerases are enzymes present in all cells that catalyze topological changes in DNA. Topoisomerase II (“topo II”) plays important roles in DNA replication, chromosome segregation and the maintenance of the nuclear scaffold in eukaryotic cells. The enzyme acts by creating breaks in DNA, thereby allowing the DNA strands to unravel and separate. Due to the important roles of the enzyme in dividing cells, the enzyme is a highly attractive target for chemotherapeutic agents, especially in human cancers.
Topo II and Hsp90 belong to a small group of proteins that share the same ATP binding domain known as the Bergerat fold. Recently, it has been reported that the Hsp90 inhibitor, radicicol, can inhibit the activity of human topo II, most likely by interacting with the ATP-binding site of the enzyme. Gadelle, D., et al., Biochemical Pharmacology, (2006), doi:10.1016/j.bcp.2006.07.040.
Topo II inhibitors are known to have various side effects and resistance often develops. Therefore, a need exists for new topo II inhibitors which may reduce some of the side effects associated with known topo II inhibitors.